Anaphylaxis affects up to 2% of the United States population,1 with an estimated lifetime prevalence in Western countries of 0.05% to 2.0%.2 A recent Monte Carlo simulation of the societal burden of anaphylaxis in the United States estimated the at-risk population to be 14.4 million (3.7 million to 48.7 million) people.3

The incidence of anaphylaxis is rising in developed countries, particularly in young children.4 The precise incidence and prevalence vary considerably due to differing definitions of anaphylaxis as well as underdiagnosis, underreporting and other factors.1 Given this, nurse practitioners and physician assistants must be vigilant in identifying both adult and pediatric patients at risk for anaphylaxis and work to educate them about responding to anaphylactic emergency.

Case Example

A 50-year-old woman with hypertension (controlled by beta-blocker therapy) and allergic rhinitis to dust mites presented to an urgent-care facility complaining of a "lump in the throat," difficulty swallowing, voice change, lightheadedness, chest tightness, cramping abdominal pain, and diffuse pruritus with red raised rash on her face and torso. Symptoms were noted approximately 30 minutes after lunch, during which the patient had eaten shrimp with cashews and fried rice at a restaurant. The patient had tolerated shrimp and other tree nuts in the past without reactions, however, she had not eaten cashews for years. The patient reported no history of food allergies and said she did not drink alcohol or exercise prior to or after lunch. Her family history is significant for a sister with food allergies.

On physical exam, the patient appeared anxious, pale and in moderate respiratory distress. Her voice was hoarse, and she could not talk in complete sentences. The patient was hypotensive (88/48 mm Hg), tachycardic (140 bpm), hypoxic (O2 saturation 90% on room air) and tachypneic (35 breaths per minute). No oropharyngeal angioedema was visible, but an urticarial rash was present on her face and torso. Chest auscultation demonstrated inspiratory and expiratory wheezing. Heart rhythm was regular, but her pulse was weak. The abdomen was soft, and hyperactive bowel sounds were noted. The patient was diagnosed with anaphylaxis.

Overview of Anaphylaxis

Several prominent allergy organizations have reached consensus on a definition for anaphylaxis: an acute, life-threatening systemic reaction with varied mechanisms, clinical presentations and severity that results from the sudden systemic release of mediators from mast cells and basophils.5 Anaphylaxis is classified based on immunologic, nonimmunologic and idiopathic mechanisms, which are initiated by different triggers.6

Triggers of anaphylaxis include food, medications, insect venom, latex and chemicals commonly found in food and household products. Cardiac arrest may occur rapidly after exposure to an allergen - within 30 minutes after exposure to food, 15 minutes after exposure to venom, or 5 minutes after exposure to iatrogenic allergens.7 Triggers must be identified by a detailed history of exposures; skin testing and specific in vitro testing may be used for confirmation.5 A lack of or minimal reaction to a food or other allergens on previous exposure does not guarantee similar safety in later exposures.

Food Allergy

Food is the most common trigger for anaphylaxis in children and teenagers.8,9 Food allergy prevalence is on the rise, with an 18% increase over the past decade.10,11 Eight foods are responsible for approximately 90% of reactions: peanuts, tree nuts, fish, shellfish, egg, wheat, cow milk and soy.10,12 Herbal products, including some dietary supplements, also have been implicated as triggers.13

Food allergens are responsible for 30% of fatal cases of anaphylaxis.5 The risk for fatal anaphylaxis increases when triggers are tree nuts or peanuts, when patients are young adults or adolescents, or when epinephrine is not administered in a timely manner.5

There is no cure for food allergy; allergen avoidance and treatment of acute reactions are the only options. Thus, identification of triggers, vigilant avoidance and preparedness to manage reactions are of utmost importance. Most reactions in patients with known food allergy are due to unintentional exposure.10 Food dishes may pose special challenges due to hidden or cross-reacting allergens or contamination after cross-contact with an allergen.13

Medications

Medications, radiocontrast agents and other drugs are the second most common trigger and the primary trigger in adults.5 Many medications are capable of causing anaphylaxis, including members of these therapeutic classes: anesthetics, neuromuscular blockers, hypnotics, opioids, antineoplastics, antibiotics and biologics.14

Among medications, penicillin is the most common trigger.5 Approximately 4% of patients who are allergic to penicillin react to cephalosporins as well. After antibiotics, aspirin and nonsteroidal anti-inflammatory drugs are the second most common drug groups implicated in anaphylactic reactions.

Insect Venom

Anaphylaxis triggered by insect venom occurs in 3% of adults and 1% of children.5 This can be fatal even in the initial reaction.5 Insects that commonly cause anaphylaxis in North America belong to the order Hymenoptera15 andinclude honeybees, yellow jackets, hornets, wasps, bumblebees and fire ants.5

Latex and Chemicals

Latex and other industrial products also can cause anaphylaxis. Populations at risk include healthcare workers, other workers with occupational exposure to rubber, and children who have urinary catheters (for spina bifida, genitourinary abnormalities, etc.).5 Allergic manifestations range from localized reactions at the site of exposure to life-threatening reactions with multisystem involvement. Published case reports have implicated multiple other chemicals, such as preservatives, food dyes and additives, and drug contaminants.13

Risk Factors

Concomitant conditions and certain medications may increase the severity of anaphylactic symptoms, mortality risk and resistance to treatment.5,10 In children, asthma is associated with a fourfold increase in food allergy risk.16 The risk of anaphylactic reaction is higher with increased asthma severity.17 Adolescence, associated with risky behaviors such as alcohol ingestion, lack of vigilance in trigger avoidance, ignorance of symptoms, and refusal to comply with an action plan, also increases risk. Table 1 summarizes factors that may potentiate anaphylaxis risk or severity.6

Diagnosis

Table 2 illustrates the criteria for diagnosis of anaphylaxis developed by the National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and Anaphylaxis Network (FAAN).6(Note: In November 2012, FAAN merged with the Food Allergy Initiative under the name Food Allergy Research & Education [FARE].) These criteria are 96.7% sensitive and 82.4% specific for emergency department (ED) diagnosis of anaphylaxis.15,18

Rapid recognition of anaphylaxis is paramount, since failure may lead to fatality. Accurate diagnosis may be challenging because the NIAID-FAAN criteria are underused and various clinical manifestations and multisystem involvement (Table 3)may present similarly to many other acute conditions.5 It is important to recognize gastrointestinal features of anaphylaxis in addition to better known dermatologic, respiratory and cardiovascular symptoms.

Atypical features may complicate diagnosis. In certain populations, such as infants and toddlers, clear communication is lacking and behavioral changes may be initial signs of a systemic allergic reaction.

The time course of anaphylaxis may be variable, ranging from onset of symptoms immediately after allergen exposure to hours later. A biphasic reaction (recurrence of symptoms after apparent resolution) may occur 1 to 72 hours after the initial manifestation.5 Biphasic reactions occur in 25% or less of fatal or near-fatal allergic reactions. Protracted, severe anaphylaxis may last for days despite aggressive treatment.10,19

The list of differential diagnoses (Table 4) is vast and includes nonhistaminergic conditions and reactions due to excess histamine, whether exogenous or endogenous.5,20 As stated previously, it is of paramount importance that possible triggers be evaluated through a careful interview of the patient, but a trigger may not be readily evident in all cases.

Case Continued

Returning to the case example, the patient was placed in a supine position with lower extremities elevated. She received epinephrine 0.3 mg (0.3 mL of 1:1000 dilution) intramuscularly (IM) into the left anterolateral thigh. Nebulized albuterol 2.5 mg via oxygen at 10 L/min was also administered, followed by oxygen at 4 L/min by nasal cannula and diphenhydramine 50 mg IM. A peripheral intravenous line was inserted, with normal saline to keep the vein open. The patient remained hypotensive and tachycardic, so a second dose of epinephrine 0.3 mg was administered IM 5 minutes after the first dose.

Glucagon was ordered due to the patient's beta-blocker therapy, which could interfere with epinephrine treatment. In 5 minutes, the patient's blood pressure rose, she became less anxious and reported a diminished sensation of a "lump in the throat."

Serum total tryptase level was obtained but results were not immediately available. The patient received prednisone 40 mg by mouth in an attempt to prevent a biphasic reaction. The patient was observed for 3 hours after her vital signs stabilized and symptoms resolved. After the observation period, the patient was discharged home in stable condition on diphenhydramine 25mg to 50 mg every 4 to 6 hours as needed. A prescription for two epinephrine autoinjectors was provided, along with instructions on proper use and indications. She was advised to avoid shellfish and tree nuts. An action plan was provided to the patient, and the patient was advised to follow up with an allergist.

Treatment

Prevention through trigger avoidance is the keystone of management in patients with a history of, or who are at risk for, anaphylaxis.5

When anaphylaxis does occur , IM epinephrine is considered first-line treatment.5,21,22 The dose of epinephrine is 0.01 mg/kg (dilution 1:1000) to a maximum of 0.5 mg in adults and 0.3 mg in children when using ampules.13 However, in clinical practice the 0.3-mg autoinjector should generally be used for patients weighing 30 kg or more (66 pounds or more) and the 0.15-mg device used with weights of 15 kg to 30 kg (33 to 66 pounds).23 Epinephrine should be administered in the midanterolateral thigh, and doses may be repeated after 5 to 15 minutes if symptoms are ongoing or progressive. Approximately 10% to 20% of patients may require repeated dosing.10

The patient should be placed in a supine position, with lower extremities elevated, to minimize effects of potential cardiovascular collapse.5 Respiratory support (supplemental oxygen and bronchodilators) should be readily available. Vital signs should be monitored frequently, including pulse oximetry.5,10 Healthcare providers should have a low threshold for transferring the patient to a higher-level facility if symptoms continue after initial treatment.

H1 or a combination of H1 and H2 antihistamines may be used as an adjunct to epinephrine.5,10 If antihistamines are used alone for milder reactions, observe the patient for an adequate time to ensure lack of progression. However, if the patient has a history of severe allergic reaction, epinephrine should be administered promptly at the onset of even mild symptoms.10 Corticosteroids may be used to prevent protracted or biphasic reactions, although little data support this. Use should not alter the decision to transfer a patient with inadequate response to epinephrine.

Follow-Up

Every patient who experiences an anaphylactic reaction should receive a prescription for two epinephrine autoinjectors to ensure adequate coverage for biphasic or protracted anaphylaxis. It may be helpful to call patients the next day to be sure they have filled prescriptions. It is optimal for patients and caregivers to have more than one epinephrine prescription for different locations, such as school, daycare and the workplace.

Patient Education

Patients are more likely to adhere to management plans when they understand the seriousness of their condition, the reasons for prescribed medications, the risks of delayed use of epinephrine, and the consequences of nonadherence. NPs and PAs are well qualified to provide such education, to address patients' concerns and to assess understanding.

Instructions for use vary according to the autoinjector used, so individualized training with the prescribed device and return demonstration by the patient/caregiver is needed. Technique should be assessed regularly by asking the patient or caregiver to demonstrate use of a trainer device. The ability to demonstrate how to use the autoinjector was one of the most important factors in transferring responsibilities for epinephrine use from adults to children.21

An individualized action plan should be created and reviewed regularly with the patient and caregiver. Examples are available from the American Academy of Allergy, Asthma and Immunology (https://www.aaaai.org/) and FARE (http://www.foodallergy.org/). Such plans include a list of the patient's allergies, triggers and relevant concomitant conditions; a description of anaphylaxis symptoms; instructions on when to use an epinephrine autoinjector; and when to follow up in the ED or office.

Three epinephrine autoinjectors are now available in the United States.23-25 EpiPen has been available for 25 years and is prescribed in 0.30 mg and 0.15 mg (EpiPen Jr.) doses. Each prescription contains two autoinjectors and a placebo trainer.

Auvi-Q was approved in 2012 and became available in 2013. It is dispensed in cartons of two injectors containing 0.30-mg or 0.15-mg doses and a trainer device. The Auvi-Q provides audible instructions when activated, literally "talking patients through" administration. It is shaped like a stack of credit cards and smaller than a smart phone.

The third option is Adrenaclick. This autoinjector, which entered the market in 2013, is available in 0.30-mg and 0.15-mg doses. Two devices are packed in a carton. A trainer device can be ordered without charge from the company. An authorized generic is available for Adrenaclick.26

Training videos and trainer devices for all autoinjectors are available on the Internet. However, patient and caregiver education is critical with each of these devices because they are each activated differently. Selection of the device may be according to patient preference or insurance coverage. If changing devices, the patient or caregiver should be appropriately instructed.

Practice Implications

The ability to rapidly recognize manifestations of anaphylaxis and the prompt administration of epinephrine are the most important factors in ensuring a favorable outcome. NPs and PAs play an important role in diagnosis and treatment and a particular role in educating patients and caregivers to ensure adequate preparation for an anaphylactic event.

Gabriel Ortiz is a physician assistant at Pediatric Pulmonary Services in El Paso, Texas. Mary Lou Hayden is a nurse practitioner and certified asthma educator at Breathe America Richmond in Glen Allen, Va. The authors have completed disclosure statements and report the following: Ortiz is a consultant to Genentech, Merck, Mylan, Teva and Sunovion, and he is a member of the speaker bureaus for Aerocrine, Genentech, Merck, Mylan, ThermoFischerScientific, Teva and Sunovion. Hayden is a consultant to Mylan, Teva, Sunovion and Genentech, and a member of the speaker bureaus for Mylan, Teva, Sunovion and Genentech. The authors also reported that Andrey Leonov, MD, an agent of PharmaWrite, LLC, provided professional medical writing assistance to them. Mylan Specialty provided funding for medical writing assistance but had no role in the development or content of the manuscript.

References

1. Lieberman P, et al. Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol. 2006;97(5):596-602.

21. Simons E, et al. Timing the transfer of responsibilities for anaphylaxis recognition and use of an epinephrine auto-injector from adults to children and teenagers: pediatric allergists' perspective. Ann Allergy Asthma Immunol. 2012;108(5):321-325.

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